Proceedings of the National Academy of Sciences of the United States of America 20120416 19

Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Intriguingly, mitochondrial gene expressio ...[more]

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Project description:The purpose of this study is to investigate the role of SIRT1 in high-fat diet-induced liver steatosis and insulin resistance. SIRT1 is a nuclear enzyme that could remove an acetyl-group from target proteins by using NAD as co-substrate. Homologs of this protein in yeast and the roundworm C. elegans are able to delay the aging process in response to nutrients. However, the molecular mechanism by which SIRT1 sense the environment to mediate this response are poorly understood. We have shown that when chronically fed with a 40%-fat diet, SIRT1 heterozygous animals gain significantly more weight compared to wild type littermates. They are also hyperinsulimia, more insulin-resistant, and accumulate more lipids in liver. Interestingly, these animals also show signs of premature aging, such as an early appearance of gray fur, defective motor activity, and decreased fertility. In this microarray study, we analyzed the gene expression profiles in the liver of WT low-fat diet, Het low-fat diet, WT high-fat diet, and Het high-fat diet using Agilent Whole Genome Mouse 4x44 multiplex format oligo arrays following the Agilent-1-color microarray-based gene expression analysis protocol. This microarray analysis concluded that SIRT1 Het mice reponsed to the high-fat diet differently from the WT control mice. Liver total RNAs from SIRT1 WT and Het mice that were fed with either a low-fat diet or a high-fat diet for 34 weeks were used for a microarray gene expression study. Three biological replicates for each group were used.